Capsaicin

Identification

Name

Capsaicin

Accession Number

DB06774 (DB05674, DB05318)

Type

Small Molecule

Groups

Approved

Description

Capsaicin is most often used as a topical analgesic and exists in many formulations of cream, liquid, and patch preparations of various strengths; however, it may also be found in some dietary supplements. Capsaicin is a naturally-occurring botanical irritant in chili peppers, synthetically derived for pharmaceutical formulations. The most recent capsaicin FDA approval was Qutenza, an 8% capsaicin patch dermal-delivery system, indicated for neuropathic pain associated with post-herpetic neuralgia.

Pharmacology

Indication

The capsaicin 8% patch is indicated in the treatment of neuropathic pain associated with post-herpetic neuralgia. There are multiple topical capsaicin formulations available, including creams and solutions, indicated for temporary analgesia in muscle and join pain as well as neuropathic pain.

Capsaicin is a TRPV1 receptor agonist. TRPV1 is a trans-membrane receptor-ion channel complex activated by temperatures higher than 43 degrees Celsius, pH lower than 6, and endogenous lipids. When activated by a combination of these factors, the channel can transiently open and initiate depolarization due to the influx of calcium and sodium ions. Because TRPV1 is commonly expressed in A-delta and mostly C fibers, depolarization results in action potentials which send impulses to the brain and spinal cord. These impulses result in capsaicin effects of warming, tingling, itching, stinging, or burning. Capsaicin also causes more persistent activation of these receptors compared to the environmental agonists, resulting in a loss of response to many sensory stimuli, described as "defunctionalization". Capsaicin is associated with many enzymatic, cytoskeletal, and osmotic changes, as well as disruption of mitochondrial respiration, impairing nociceptor function for extended periods of time.

Mechanism of action

Capsaicin has been shown to reduce the amount of substance P associated with inflammation - however this is not believed to be its main mechanism in the relief of pain [4]. Capsaicin's mechanism of action is attributed to "defunctionalization" of nociceptor fibers by inducing a topical hypersensitivity reaction on the skin. This alteration in pain mechanisms is due to many of the following: temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fiber terminals.

Oral: Following oral administration, capsaicin may be absorbed by a nonactive process from the stomach and whole intestine with an extent of absorption ranging between 50 and 90%, depending on the animal [4]. The peak blood concentration can be reached within 1 hour following administration [4]. Capsaicin may undergo minor metabolism in the small intestine epithelial cells post-absorption from the stomach into the small intestines. While oral pharmacokinetics information in humans is limited, ingestion of equipotent dose of 26.6 mg of pure capsaicin, capsaicin was detected in the plasma after 10 minutes and the peak plasma concentration of 2.47 ± 0.13 ng/ml was reached at 47.1 ± 2.0 minutes [4].

Systemic: Following intravenous or subcutaneous administration in animals, the concentrations in the brain and spinal cord were approximately 5-fold higher than that in blood and the concentration in the liver was approximately 3-fold higher than that in blood [4].

Topical: Topical capsaicin in humans is rapidly and well absorbed through the skin, however systemic absorption following topical or transdermal administration is unlikely [4]. For patients receiving the topical patch containing 179 mg of capsaicin, a population analysis was performed and plasma concentrations of capsaicin were fitted using a one-compartment model with first-order absorption and linear elimination. The mean peak plasma concentration was 1.86 ng/mL but the maximum value observed in any patient was 17.8 ng/mL [4].

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Capsaicin metabolism after oral administration is unclear, however it is expected to undergo metabolism in the liver with minimal metabolism in the gut lumen. In vitro studies with human hepatic microsomes and S9 fragments indicate that capsaicin is rapidly metabolized, producing three major metabolites, 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, whereas vanillin was a minor metabolite [4]. It is proposed that cytochrome P450 (P450) enzymes may play some role in hepatic drug metabolism [4]. In vitro studies of capsaicin in human skin suggest slow biotransformation with most capsaicin remaining unchanged.

Route of elimination

It is proposed that capsaicin mainly undergoes renal excretion, as both the unchanged and glucuronide form. A small fraction of unchanged compound is excreted in the feces and urine. In vivo animal studies demonstrates that less than 10 % of an administered dose was found in faces after 48 h [4].

Half life

Following oral ingestion of equipotent dose of 26.6 mg of pure capsaicin, the half life was approximately 24.9 ± 5.0 min [4]. Following topical application of 3% solution of capsaicin, the half-life of capsaicin was approximately 24 h [4]. The mean population elimination half-life was 1.64 h following application of a topical patch containing 179 mg of capsaicin [4].

Clearance

Not Available

Toxicity

Acute oral LD50 and dermal LD50 in mouse are 47.2 mg/kg and >512 mg/kg, respectively [MSDS]. Capsaicin is shown to be mutagenic for bacteria and yeast [MSDS].

Capsaicin can cause serious irritation, conjunctivitis and lacrimation via contact with eyes. It induces a burning sensation and pain in case of contact with eyes and skin. As it is also irritating to the respiratory system, it causes lung irritation and coughing as well as bronchoconstriction. Other respiratory effects include laryngospasm, swelling of the larynx and lungs, chemical pneumonitis,respiratory arrest and central nervous system effects such as convulsions and excitement [5]. In case of ingestion, gastrointestinal tract irritation may be observed along with a sensation of warmth or painful burning [MSDS]. Symptoms of systemic toxicity include disorientation, fear, loss of body motor control including diminished hand-eye coordination, hyperventilation, tachycardia, and pulmonary oedema [5]. Careful early decontamination is recommended and medical intervention should be initiated for any life-threatening symptoms. In case of contact, individual must be removed from the source of exposure and the contacted skin and mucous membranes should be thoroughly washed with copious amounts of water [5].

Acts as a mediator of transcriptional repression by nuclear hormone receptors via recruitment of histone deacetylases (By similarity). Functions as an estrogen receptor (ER)-selective coregulator that potentiates the inhibitory activities of antiestrogens and represses the activity of estrogens. Competes with NCOA1 for modulation of ER transcriptional activity. Probably involved in regulating mitochondrial respiration activity and in aging.